Reduced folate carrier polymorphism (80A→G) and neural tube defects

Abstract

Transport of folates in mammalian cells occurs by a carrier-mediated mechanism. The human folate carrier (RFC-1) gene has been isolated and characterized. Within this gene, a common polymorphism, 80A-G, changing a histidine to an arginine in exon 2 (H27R), was recently identified. Defects in folate metabolism, such as defective carrier molecules, could be implicated in the etiology of neural tube defects (NTDs). In the present case-control study, we recruited 174 Italian probands with nonsyndromic NTD, 43 mothers, 53 fathers and 156 control individuals and evaluated the impact of RFC-1 variant on NTD risk. A statistically significant risk was calculated for the 80GG genotype of the NTD cases (OR ¼ 2.35; 95% CI 1.21-4.58) and mothers (OR ¼ 2.74; 95% CI 0.92-8.38). On the contrary, the heterozygous genotype of the mothers and both heterozygous and homozygous genotypes of the fathers did not seem to be significant NTD risk factors. Furthemore, according to the multifactorial inheritance of NTDs, we demonstrated that the combined genotypes for MTHFR 1298A-C and RFC-1 80A-G polymorphisms of cases resulted in greater NTD risk than heterozygosity or homozygosity for RFC-1 80A-G variant alone. Conversely, our data provide no evidence for an association between NTD phenotype and combined MTHFR C677T/RFC-1 A80G genotypes. Moreover, here we describe the combinations of the two MTHFR polymorphic sites (677CT and 1298AC) with RFC-1 genotypes. We found that both patients and controls could have at most quadruplemutation combinations. Interestingly, 27% (7/26) of the mothers and 18.75% (30/160) of the cases genotyped presented four mutant alleles in comparison with 8.5% (11/129) of the controls. Finally, the frequency of NTD cases and mothers carrying combined heterozygosity for the two MTHFR polymorphisms and RFC-1 80GG homozygosity (677CT/1298AC/80GG) (cases ¼ 11.3%; mothers 11.5%) was increased compared with controls (1.6%). Altogether, our findings support the hypothesis that RFC-1 A80G variant may contribute to NTD susceptibility in the Italian population.

Metabolic endophenotype and related genotypes are associated with oxidative stress in children with autism

“…The G allele (glutamine>arginine) has been associated with increased risk of birth defects (De Marco et al 2003) and elevated plasma folate as the result of impaired cell uptake (Yates and Lucock 2005). Relative to controls, autistic children had a significant increase in the frequency of the reduced folate carrier RFC-1 homozygous 80GG (33% vs. 26%) and heterozygous 80GA (52% vs. 41%).…”

The association of idiopathic recurrent early pregnancy loss with polymorphisms in folic acid metabolism-related genes

“…MTRR A66G is involved in onecarbon metabolism, but has not been studied extensively in RPL etiology. Considering the SLC19A1 gene encodes the RFC1 protein, it is plausible that polymorphism in SLC19A1 gene may interfere with the folate transporting by means of reduced SLC19A1 protein expression (De Table 2 continued Genotype and allele Marco et al 2003;Relton et al 2003). The effects of SLC19A1 G80A polymorphism on cellular folate intake remain uncertain (Whetstine et al 2001;StanislawskaSachadyn et al 2009); however, the G allele of G80A has been suggested as a risk factor for HHcy (Chango et al 2000;Altmae et al 2010), which is speculated to be associated with defective chorionic villous visualization in women with RPL (Nelen et al 2000).…”

Investigation of inter-individual variability of the one-carbon folate pathway: a bioinformatic and genetic review

“…76 This same p.H27R polymorphism has also been identified as a risk factor for NTDs. [77][78][79] An effect on absorption and cellular translocation, and blood pressure, in the elderly has also been described. 80 FOLR1 polymorphisms have been described earlier as susceptibility factors for gastric cancer in a Chinese population.…”